New method extracts important mutations from enhancer DNA

A team of researchers led by scientists at the Whitehead Institute have just published data concerning the DNA that regulates the on/off state of genes noting that it is critically important in cancer and that even small mutations can have outsized effects on cancer when this DNA is altered. The findings from this new study were published online today in Nature Communications through an article entitled “Small genomic insertions form enhancers that misregulate oncogenes.”

The Whitehead researchers have previously shown that one small mutation could build a potent enhancer—a regulatory DNA element that controls gene function—but the extent to which this phenomenon occurred across all cancers had been unknown. Now the investigators suggest that small mutations that hijack oncogene control occur far more frequently than previously appreciated. The team found insertion mutations of only a few nucleotides in the enhancers of 102 different cancer samples and predicted that many of them are likely to misregulate oncogenes.

“Here, using a combination of Chip-seq to enrich enhancer DNA and a computational approach with multiple DNA alignment procedures, we identify enhancer-associated small insertion variants,” the authors wrote. “Among the 102 tumor cell genomes we analyze, small insertions are frequently observed in enhancer DNA sequences near known oncogenes. Further study of one insertion, somatically acquired in primary leukemia tumor genomes, reveals that it nucleates the formation of an active enhancer that drives expression of the LMO2 oncogene.”

A newly developed pipeline next uncovered the mutations in these purified enhancers. Surprisingly to the team, many mutations were uncovered by looking in the “scrap heap” of sequencing data normally ignored by biomedical researchers for technical reasons.

“Only a tiny fraction of the genome has enhancer activity in a given cell, so being able to shrink the haystack really helped find the needles within it,” explained the study’s lead author Brian Abraham, Ph.D., a post-doctoral researcher at Whitehead Institute.

This new study provides a large catalog of small insertions that may guide researchers to additional discoveries of genes that play important roles in cancer.

“Understanding both the genes that are misregulated by a mutation in cancers and the ways in which they become misregulated are key to finding treatment-targetable aspects of cancers,” noted senior study author Richard Young, Ph.D., a member of Whitehead Institute and professor of biology at Massachusetts Institute of Technology.

The research team combined experimental and computational tools to build a catalog of enhancer-altering mutations across these samples. They first purified and sequenced the DNA of enhancers.